Dallas—Testosterone-replacement therapy increased risks of death, heart attack, or ischemic stroke in veterans who underwent coronary angiography and had low serum testosterone levels, according to a new study.

The Veterans Administration (VA)-funded study, published this month in the Journal of the American Medical Association, evaluated the association between the use of testosterone therapy and all-cause mortality, myocardial infarction, and stroke among male veterans and whether this association was modified by underlying coronary artery disease (CAD).

Led by researchers from University of Texas Southwestern Medical Center in Dallas, the study involved 8,709 VA patients with low testosterone levels of less than 300 ng/dL who underwent coronary angiography between 2005 and 2011. Participants had high levels of coexisting illnesses, including prior history of heart attack, diabetes, or CAD.

Of the patients, 14% (1,223) started testosterone therapy after a median of 531 days following angiography. After average follow-up of about 2 years and 3.5 months, the primary measured outcome for the study was a composite of all-cause mortality, heart attack, and ischemic stroke.

Results indicate that 19.9% of patients who had not used testosterone-replacement therapy experienced coronary events 3 years after angiography compared to 25.7% in the testosterone therapy group. The groups had similar blood pressure, low-density lipoprotein levels, and use of secondary prevention medications, although the control group actually was slightly older, average age 64, than the testosterone replacement group at average age of 61.

Researchers point out that, even after taking into account other factors that could explain the differences, use of testosterone therapy was associated with adverse outcomes and was consistent among patients with and without CAD.

Those risks should be discussed with patients considering testosterone replacement therapy “in terms of what the benefits are and what the potential risks are,” said coauthor P. Michael Ho, MD, PhD, of the VA Eastern Colorado Health Care System in Denver.

The article notes that an estimated 2.9% of U.S. men over 40-years-old are prescribed testosterone therapy, despite the lack of an extensive randomized trial examining the long-term benefits and risks.

Writing in an accompanying editorial, Anne R. Cappola, MD, ScM, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia raised the issue of whether the research can be generalized to “the broader population of men taking testosterone: men of this age group who are taking testosterone for ‘low T syndrome’ or for antiaging purposes and younger men taking it for physical enhancement.”

“Are the benefits—real or perceived—for these groups of men worth any increase in risk? These populations represent a sizable group of testosterone users, and there is only anecdotal evidence that testosterone is safe for these men,” she writes.

“There is mounting evidence of a signal of cardiovascular risk, to which the study by Vigen et al contributes,” Cappola adds. “This signal warrants both cautious testosterone prescribing and additional investigation.”